Project Summary Alzheimer?s dementia (AD) is the most common form of neurodegenerative disease and is characterized histopathologically by the accumulation of amyloid beta (A?) and tau peptides in the brain and central nervous system (CNS). The risk of developing AD increases dramatically with age, with an estimated 5.2 million of the 5.4 million patients suffering from AD over 65 years of age. This suggests that A? production or clearance mechanisms may be affected by the aging process. Indeed, it has been shown that while the production of A? remains relatively stable in the aging and AD brain, its clearance from the central nervous system is markedly reduced in both the aging and AD brain. This suggests that a breakdown in A? clearance mechanisms underlies the accumulation of A? in the aging and AD brain. Recently, a meningeal lymphatic vascular system that absorbs solutes from the brain interstitium and cerebrospinal fluid was reported by two independent laboratories. This discovery has important implications for our understanding of interstitial homeostasis in the brain and CNS, and is a previously unstudied pathway for A? removal from the brain and cerebrospinal fluid. We recently confirmed the translational relevance of these findings in a cohort of human AD subjects, wherein we identified that the majority of human meningeal samples, with and without AD, also contain lymphatic vessels. Though it has been demonstrated that this understudied anatomical pathway exists in humans, the functional importance of the meningeal lymphatic system in the context of A? removal from the brain and CSF is unknown. We hypothesize that reduction in lymphatic clearance of A? from the CNS underlies the accumulation of A? in the aging and AD brain. By measuring lymphatic clearance of A?1-40 from the CNS in young and aged mice, this proposal will determine the effect of aging on the meningeal lymphatic system in the development of AD pathology. This proposal will also combine in vivo microdialysis, transgenic murine models of AD, and novel adeno-associated virus gene delivery to modulate lymphatic function in the setting of AD. Together, using these direct strategies to study meningeal lymphatic function, we will evaluate the role of lymphatic function in the clearance of A?. This will be the first study to investigate a causal relationship between the function of the meningeal lymphatic system and the accumulation of A? in the brain, and will generate multiple tools for studying the function of the meningeal lymphatic vasculature in other neurological diseases.